Process for the production of substituted lactams



United States 1 Patent:

This invention relates to a novel process for .the production of lactams having the following structural formula:

Rt wherein R and R each represents hydrogen or lower alkoxy such as methoxy, ethoxy, or propoxy, R represents hydrogen or lower alkyl such as methyl, ethyl,

'propyl or butyl and R represents hydrogen, hydroxy,

or keto, and n is an integer of 1 or 2.

These substituted lactams are important intermediates for the production of 8-azasteroids, the preparation of which is described and claimed in our co-pending application Serial No. 248,872, filed January 2. 1963. In addition, these lactams can also be used as starting materials for other substituted quinolizines.

in accordance with this invention, these lactams are produced by the following reaction steps. The symbols R R R and R used hereinafter in describing said reactions have the same meaning as defined above.

Step 1 comprises reacting an appropriately substituted p-phenethylamine with cyclic keto acid in a low boiling water-immiscible solvent under the conditions of water removal such as by the use of a Dean-Stark trap. The reaction may be represented by the equation:

Low boiling water immiscible solvents which may be conveniently employed in this reaction are for example methylene chloride, chloroform, or benzene. I

The resulting Schiffs base obtained in accordance with Step 1 is preferably treated directly without isolation with an equal molar ratio of a substituted carbodiimide of the formula R-N==C==N--R' in which R may be a mono- 3,265,700 Patented August 9, 1966 ice valent polar radical such as cyclohexyl. isopropyl, iso butyl, and the like. N,N'-dicyclohexylcarbodiimide is commercially available and is therefore the preferred re agent of choice. The treatment of the Schiti's base with the carbodiimide results in the formation of an amide bond between the carboxyl group and the nitrogen atom to give the desired lactams. The reaction is expressed by the following equations:

The lactams obtained may then by cyclized to give 8- azasteroids as described in said co-pending application. Thus for example the lactam may be treated with phosphorous oxyehloride to give an 8-azasteroid of the formula:

In order to further illustrate this informatic n, the following examples are given:

EXAMPLE 1 '1 A solution of 45.5 g. of Z-(IS-carboxyethyl)-2-methyl- 1,3-cyclopentanedionc and 37.8 g. of m-methoxyphcnethylamine in 2.5 liters of methylene chloride is refluxed for 2 /2 hours under a modified Dean-Stark trap. A solution of 51.5 g. of dicyclohexylcarbodiimide in ml. methylene chloride is then added slowly. The resulting slurry is refluxed with stirring for 10 minutes, then cooled for 16-24 hours at 10 C. The slurry is filtered and the filtrate poured directly onto 3.75 kg, of alumina. The column is washed with 16 liters of methylene chloride and the solvent removed from this fraction to give 4,4a dihydro-l-(m-methoxyphenethyl)-4a-methyl-lH-1- pyrindine-2,5-(3H,6H)-dione in the form of a pale yellow oil.

3 EXAMPLE 2 4,4a-di/i ydro-l 3 ,4-dimethoxyphenethyl -4a-methyl- IIl-I -pyrinrlinc-2,5-(3,611)-di0ne In the same way as described in Example 1, 18.1 g. of homoveratrylamine and 18.4 g. of Z-(flcarboxyethyh- Z-methyl-l,3-cyclopentancdione on treatment with 20.6 g. of dicyclohexylcarbodiimide gave 4,4a-dihydro-1-(3,4- diniethoxyphenethyl) 4a methyl-lH-1-pyrindine-2,5- (3H,6H)-dione as white crystals, M.P. 75-6 after recrystallization from ether.

It is to be understood that the foregoing detailed description is given merely by Way of illustration and that many variations may be made therein without departing from the spirit of our invention. 7

Having described our-invention, what we desire to secure by Letters Patent is: 7

Process for the production of a compound of the formula:

wherein R and R is each a member selected from the group consisting of hydrogen and lower alkoxy, R is lower alkyl, R; is a member selected from the group consisting of hydrogen, hydroxy and keto and n is an integer of from 1 to 2, which comprises contacting a compound of the formula:

with a compound of the formula R'N C N--R in which R is a member selected from the group consist- 15 ing of isopropyl, cyclohexyl and isobutyl.

References Cited hythe Examiner Ziman: Chem. Abstracts, vol. 46, page 6084 (1952).

ALEX MAZEL, Primary Examiner. NICHOLAS S. RIZ ZO, HENRY R. JILES, Examiners. R. D. PRICE, D. G. DAUS, Assistant Examiners. 

